Thymosin alfa-1 (Tα1): regulation of the immune system, clinical trials and new directions for experimental research

What is thymosin alpha-1?

Thymosin alfa-1 (Tα1), also known as thymalfazine, is a naturally occurring peptide that was first isolated from the thymus. Its biological activity is closely related to the regulation of the immune system, including the maturation of T lymphocytes, the function of immune cells, and the coordination of inflammatory responses. The peptide has been approved for use in selected indications, including chronic viral hepatitis, in many countries. However, the registration status and the exact scope of approved indications vary depending on the jurisdiction. Approval for marketing in one country does not automatically mean permission to use in all the diseases discussed in this review.

Because immunological signaling affects neurological, hormonal, and tissue-repair pathways, scientists have begun to investigate Tα1 beyond its traditional uses in infectious diseases. Studies have included severe pancreatitis, post-vaccination responses, HIV-related immune disorders, post-transplant complications, depressive symptoms, gum tissue healing, reproductive functions, and complications of chemotherapy. A significant portion of these studies remains preliminary, and the results of animal or isolated cell experiments do not constitute evidence of clinical efficacy in humans.

The following overview presents published results by research areas, distinguishing controlled clinical trials, observational or uncontrolled human reports, and preclinical experiments. Experimental dosing regimens are described solely for the purpose of presenting the methodology of published studies, and not as recommendations for individual use.

Illustration: Molecular structure of thymalfin (PubChem [1]).

Clinical studies of thymozine alfa-1 in humans

Depression and immune disorders in common variable immunodeficiency

In a small, open-label study verifying the preliminary scientific concept, Mersha and colleagues (2025) evaluated Tα1 in five people with common variable immune deficiency (CVID) and depression. Participants received 1.6 mg daily for the first week, followed by injections twice a week for a further seven weeks. The mean scores on the depression assessment scales decreased by 52%, compared with a reduction of 36% in the comparison group receiving standard care.

The researchers also observed lower levels of interleukin 6 (IL-6) and signs of increased production of immature T lymphocytes. After discontinuing the peptide administration, depressive symptoms returned in two participants with the most severe symptoms, and some of the immunological changes weakened. Although the results suggest a possible link between the restoration of immune function and mood, a study involving five people, without blinding, does not allow determining whether Tα1 is an effective antidepressant [2].

Severe acute pancreatitis: evidence from randomized studies

Tian and colleagues (2025) conducted a comprehensive analysis of five randomized controlled studies involving 706 patients with severe acute pancreatitis. Compared with standard treatment, the use of Tα1 was associated with higher values for CD4⁺ T lymphocytes (mean difference [MD] 4.53) and an improvement in the CD4⁺/CD8⁺ ratio (MD 0.42).

The subgroup analysis showed a decrease in C-reactive protein (CRP) levels at lower dose levels (MD −30.12 mg/l), while no significant change was observed in the groups receiving higher doses. Non-respiratory infections occurred less frequently (relative risk [RR] 0.56), including infections of the blood (RR 0.60) and infections of the abdominal cavity (RR 0.38). However, there was no significant reduction in the frequency of pulmonary infections.

The results in the APACHE II severity scale showed a slight improvement (MD −1.52), but no statistically significant reduction in hospitalization was observed. The results justify further evaluation of Tα1 as a potential adjunctive treatment in selected patients in severe conditions, rather than as a substitute for recognized methods of treating pancreatitis [3].

In an earlier randomized double-blind study, Wang and colleagues (2011) analyzed subcutaneous administration of Tα1 at a dose of 3.2 mg twice daily for seven days in patients with severe acute pancreatitis. On days 8 and 28, participants receiving the peptide observed faster recovery of HLA-DR expression on monocytes and an improvement in the CD4/CD8 ratio.

There was also a reduction in the number of positive blood and abdominal swabs, and a shorter stay in the intensive care unit. The study suggests that changes in the immune system may be associated with improvements in infection-related outcomes. However, the conclusions remain limited to the study population and the protocol used [6].

Huang and colleagues (2024) conducted a post hoc analysis to determine whether metabolic disorders influenced the response to treatment in 502 patients with acute pancreatitis. Among the 271 individuals with hyperglycemia, pancreatitis occurred within 90 days in 18.8% of the Tα1 recipients, compared with 29.7% in the placebo group. The hazard ratio was 0.80 with a 95% confidence interval of 0.37–0.97 and p = 0.03.

Similar benefits were not confirmed in patients with hypertriglyceridemia alone or in individuals with both disorders co-existing. Several analyses including additional variables supported the observed association in the subgroup. However, post hoc comparisons primarily serve to formulate hypotheses and require confirmation in prospective studies [11].

Tooth replantation and healing of periodontal tissues

Loo and colleagues (2008) studied 73 patients undergoing reimplantation of extracted teeth in a randomized, double-blind pilot study. Compared with saline, the use of Tα1 during the perioperative period was associated with lower levels of interferon, tumor necrosis factor alpha (TNF-α) and IL-6, and a higher number of leukocytes. All these differences reached the reported level of significance p < 0.05.

The researchers also described better gum healing, less tooth mobility, less occurrence of ankylosis, and longer retention of reimplanted teeth (p < 0.05). The results suggest that local or systemic modulation of immunity may affect healing after dental injuries. However, the small number of studies limits the possibility of transferring these observations to routine dental practice [4].

HIV: immune reconstitution and combination therapy

Ramachandran and colleagues (1996) evaluated Tα1 in combination with polyethylene glycol-modified interleukin 2 (PEG-IL-2) in HIV-1-infected adults who were receiving zidovudine and had a CD4 lymphocyte count of 50–250 cells/µl.

PEG-IL-2 was administered intravenously at a dose of 10⁶ IU/m² every two weeks for 20 weeks. After four administrations, Tα1 was administered once a week, gradually increasing the dose from 400 to 1600 µg/m² over two months.

During treatment with PEG-IL-2, the number of CD4 lymphocytes increased by about 30–40%, but the addition of Tα1 did not lead to further measurable increase. Virus-DNA, RNA in plasma, and p24 antigen tests did not indicate virus reactivation, and the combination was generally well tolerated. The study therefore provides stronger evidence for the possibility of using such a combination than for its additional immunological efficacy [5].

Chadwick and colleagues (2003) conducted a pilot phase II study in clinically stable adults receiving highly active antiretroviral therapy (HAART), with an HIV RNA level below 400 copies/ml and a CD4 count below 200 cells/µl.

The participants continued with HAART alone or received additional Tα1 at a dose of 3.2 mg subcutaneously twice a week for 12 weeks. The total number of CD4, CD8 and CD45 cells did not increase significantly compared to the control group. However, the number of DNA loops generated during the rearrangement of the T lymphocyte receptor (sjTREC) increased in the Tα1 group, which is considered a marker associated with the recent exit of T lymphocytes from the lymph node.

No serious safety signal related to treatment has been described. However, the increase in sjTREC should not be equated with proven long-term immune reconstitution or improvement in HIV treatment outcomes [7].

In an older, unblinded, 12-month randomized study, Garaci and colleagues (1994) compared zidovudine alone with combinations comprising interferon alfa, Tα1, or both compounds in adults with a CD4 count of 200–500 cells/µl.

The triple combination was associated with a higher number of CD4 lymphocytes and better functional parameters than zidovudine alone or any combination of the two drugs. Laboratory studies also suggested the complementary effects of Tα1 and interferon alfa on lymphocyte activity.

Because antiretroviral treatment has changed significantly since the study was conducted, its results should be considered as historical evidence from immunological studies, and not the basis for contemporary decisions regarding HIV treatment [9].

Vaccinations against influenza in older people

Ershler and colleagues (2007) reviewed animal studies and clinical trials regarding the use of Tα1 in combination with influenza vaccines in the elderly.

In the part of the analyzed studies, a higher frequency of seroconversion and higher titers of antibodies against the hemagglutinin of the influenza virus were described, with generally acceptable tolerability. However, the protocols and the populations studied differed among themselves.

The review did not show that the addition of Tα1 consistently prevents laboratory-confirmed influenza or its complications. Larger, contemporary studies would be necessary to determine its clinical significance [8].

Male sperm functions and infertility

Naz and colleagues (1995) described a multicenter study involving 68 men with infertility associated with testicular dysfunction.

After exposure to Tα1 under the tested conditions, the results of the rabbit oocyte penetration tests improved in 50 of the 68 participants, or about 76%. The reported increase in the penetration rate was between 31 and 45%, with p-values ranging from 0.0006 to below 0.0001.

The changes were correlated with the concentrations of Tα1 in the semen plasma (r = 0.65–0.74; p = 0.039–0.01).

The observations concern laboratory parameters related to fertilization, and not a proven improvement in the frequency of pregnancies or live births. Therefore, they do not confirm Tα1 as a method of treating infertility [10].

Immunological aplasia and platelet count restoration

In the comparative study described by Wanga and colleagues (2007), 27 patients received dexamethasone alone in high doses, while 39 patients received dexamethasone in combination with Tα1.

Dexamethasone was administered orally at a dose of 40 mg for four days. The combination treatment group additionally received 1.6 mg of Tα1 subcutaneously three times a week for four weeks.

Complete response was observed in 76.9% participants in the combination therapy group, compared to 44.4% in the comparator group. The sustained response after six months was 61.5% and 34.6%, respectively. Relapse occurred in 38.5% versus 65.4% participants (p < 0.05 reported).

The cytokine profile showed higher values of IFN-γ, IL-2 and TGF-β1 and lower values of IL-4 and IL-10. The concentration of TGF-β1 correlated with circulating Tα1 (r = 0.6028; p < 0.05).

The results justify further research, but they do not establish a treatment regimen for thrombocytopenia that could be widely applied in clinical practice [12].

Acute respiratory failure associated with cytomegalovirus after kidney transplantation

Ji and colleagues (2007) studied 46 kidney transplant recipients with cytomegalovirus (CMV)-associated acute respiratory distress syndrome (ARDS).

All participants received intensive rescue treatment, which included gancyklovir and appropriately selected antibacterial or antifungal medications. Additionally, 32 people received Tα1 subcutaneously at a dose of 1.6 mg daily or every other day, while 14 people did not receive this peptide.

The reported rate of effective rescue treatment was 78.1% compared to 50%, and mortality was 21.9% compared to 50%.

During the observation period, the number of CD4⁺ lymphocytes and the ratio of CD4⁺/CD8⁺ improved. In the survivors, an increase in the number of CD4⁺ and CD8⁺ cells was also observed on days 7, 14, and 21.

Small groups with unequal numbers and complex concomitant treatment mean that the results should be considered preliminary evidence for potential adjuvant treatment [13].

Immunotherapy of tumors: case report of multimodal treatment

Yu and colleagues (2024) described the case of a 48-year-old patient with treatment-resistant, metastatic, triple-negative breast cancer.

Stereotactic body radiation therapy (SBRT), PD-1 inhibitor, GM-CSF (granulocyte macrophage colony-stimulating factor), and Tα1 were used.

After two cycles, the primary tumor change decreased by approximately 79%, and the three lung metastases by almost 57%. The response met the partial response criteria according to RECIST v1.1.

The parameters of blood morphology remained stable, the CA19-9 concentration decreased, and the main reported adverse reaction was an manageable skin reaction.

Since several active anti-cancer methods were simultaneously used and the description concerned only one patient, the obtained response cannot be attributed specifically to Tα1 [14].

Peripheral neuropathy associated with chemotherapy

An and colleagues (2004) evaluated 22 people with advanced breast or lung cancer who had experienced grade 2–4 neurotoxicity associated with chemotherapy.

The participants continued regimens that included medications such as vinorelbine, cisplatin, gemcitabine, paclitaxel, carboplatin, or epirubicin. At the same time, they received Tα1 at a dose of 1.6 mg per day for four days before chemotherapy and twice a week for one to three weeks after it.

In ten participants (45.4%), an improvement to below the second degree of neurotoxicity was observed in subsequent neurological evaluations.

Due to the lack of a control group, the potential effect of the peptide cannot be distinguished from spontaneous improvement, changes in chemotherapy, or other factors [15].

Preclinical studies: animal models and laboratory experiments

Developing brain: neurogenesis, learning and immunological signaling

Wang and colleagues (2017) administered Tα1 to newly-born mice and then evaluated their cognitive functions and hippocampal development.

Animals receiving the peptide achieved better results in tasks related to learning and memory. Additionally, more intense neurogenesis in the hippocampus was observed, as well as changes in the immune balance, accompanied by an increase in the levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and insulin-like growth factor 1 (IGF-1).

In the experimentally induced model of inflammation Tα1 also appeared to protect the process of the formation of new neurons.

The source summary did not provide the experimental dose. These are results from studies on the development of the mouse brain and should not be interpreted as evidence of improvement in cognitive function in children [16].

In mouse hippocampal neuron cultures, Yang and colleagues (2003) analyzed Tα1 at concentrations of 1 and 10 µg/ml.

The exposure increased the frequency of excitatory synaptic events without an equivalent increase in the amplitude of the individual events. This pattern suggests a change in the probability of synaptic transmission, not an amplification of the individual signals.

The results indicate a cellular mechanism that requires further investigation, but do not confirm memory improvement in humans [17].

Injurious brain damage caused by a shock wave

Shi and colleagues (2020) studied rats subjected to traumatic brain injury associated with the action of a shock wave.

The animals received Tα1 at a dose of 200 µg/kg twice daily for three days or two weeks.

In terms of survival, there was a small, statistically non-significant early improvement. The animals receiving the peptide, however, achieved better results in maze tests assessing learning and spatial memory.

The smaller phosphorylation of the tau protein at the Thr205 site, the reduction of inflammation, and the smaller brain swelling were also described.

The results suggest a possible link between immune modulation and neuronal damage pathways, but they require independent replication and studies involving humans [18].

Factors originating from the placenta and early development of the nervous system

Turrini and colleagues (1998) studied the relationship between grooming and the developing nervous system.

The removal of the vagus nerve in newborn animals was associated with a weakening of NGF signaling, changes in neural connections, and a reduction in cholinergic activity.

Direct administration of Tα1 to the brain partially restored NGF-related parameters, neuronal connections, and acetylcholine-dependent activity.

Because the experiment involved an animal model in the developmental stage and direct administration to the brain, the results cannot be extrapolated to the general systemic use [19].

Inflammatory pain and signaling in the spinal cord

In the model of inflammation induced by complete Freund's adjuvant in rodents, study labeled [20] showed that Tα1 reduced mechanical allodynia and thermal hyperalgesia.

Measurements in the spinal cord indicated lower levels of IFN-γ, TNF-α, and BDNF, and reduced activity of the Wnt3a/β-catenin pathway.

The proposed mechanism involves a change in the communication between immune and neuronal signaling in the spinal cord.

The results of animal studies do not confirm the analgesic efficacy in humans nor establish a protocol for the treatment of pain [20].

Severe pancreatitis: survival and organ damage in rats

Wang and colleagues (2015) evaluated Tα1 and interferon alfa separately in rats with severe pancreatitis caused by taurocholan sodium.

Experimental interventions included intravenous administration of Tα1 at a dose of 26.7 µg/kg or interferon alfa at a dose of 4.0 × 10⁵ U/kg.

Both interventions reduced markers of pancreatic and liver damage, including AST, LDH, α-amylase and lipase, as well as procalcitonin and inflammatory cytokines TNF-α, IL-4, IL-5 and IL-18.

The parameters for CD3⁺, CD4⁺ and CD8⁺ T lymphocytes improved, and histological examinations showed less damage to the pancreas and lungs.

Mortality was 50% in untreated animals, 25% in the Tα1 group and 33% in the interferon alfa group.

The experiment provides mechanistic evidence regarding the modulation of resistance in acute organ damage, but does not constitute direct clinical evidence [21].

Yao and colleagues (2007) studied subcutaneous administration of Tα1 at a dose of 100 µg/kg immediately after inducing severe pancreatitis in rats and again after two hours.

Levels of IL-1β and TNF-α decreased, the inflammation of the pancreas was reduced, and the distribution of the subpopulation of T lymphocytes changed.

Smaller damage to the pancreas was observed in the tissue preparations, and survival after 72 hours was higher than in untreated animals.

At the same time, the activity of amylase and lipase did not change significantly. The heterogeneous results of biomarkers show why the experimental benefits should not be presented as an equal improvement of all disease parameters [22].

Mucopolysaccharidosis: inflammation and CFTR protein processing

Romani and colleagues (2017) evaluated Tα1 in mouse models of cystic fibrosis and airway epithelial cells derived from patients, containing the p.Phe508del variant of the CFTR protein.

The experiments described a reduced inflammation of the airways and an improvement in folding, maturation, and stability of CFTR, as well as chloride ion transport.

Such a combination of effects has sparked interest in a molecule that could affect both immune signaling and the function of membrane ion channels.

However, the results of studies in mice and ex vivo cells do not indicate efficacy in patients, and the described mechanisms require clinical confirmation [23].

Experiments on human sperm and the relationship between the structure and activity of the peptide

Naz and colleagues (1992) studied human sperm in laboratory tests of penetration and motility.

Synthetic Tα1 increased the ability of sperm to penetrate (p < 0.001), whereas thymozine beta-4 did not produce the same effect.

Antibodies directed against Tα1 or thymosin beta-4 also increased penetration, in some comparisons even 4.7-fold (p < 0.001).

The binding of antibodies was concentrated in the area of the acrosome. Interventions related to Tα1 altered the spontaneous and calcium-stimulated acrosomal response, the release of acrosin, and selected movement characteristics associated with hyperactivation.

The overall motility of the sperm did not change. In semen samples from men with sperm function disorders, the concentrations of Tα1 were lower than in fertile men (p = 0.002).

These are laboratory endpoints, and not evidence of improved fertility in clinical practice [24].

In another study, Naz and colleagues (1995) compared intact Tα1 with six modified peptides.

The natural molecule increased sperm penetration (p < 0.0001), and the strongest response in the described test was obtained at 0.5 µg per 100 µl.

Among the variants, the activity was retained by Tα1-Gly-NH₂ and the C-terminal fragment composed of 14 amino acids (Tα1-C14).

The results indicated the importance of the C-terminal region, while suggesting that the full peptide structure contributes to maximum activity.

None of the tested variants reduced penetration or did not change overall motility compared to controls. The data support biochemical studies of the peptide, but do not confirm effective infertility therapy [25].

Experimental diabetes and protection of pancreatic beta cells

Quiu and colleagues (2009) studied Tα1 in C57BL/6 mice with streptozotocin-induced diabetes.

The animals received intrathecally Tα1 at doses of 0.1 or 1 µg/kg per day for 35 days.

In both groups, glucose levels were lower than in untreated diabetic mice, although they did not return to normal levels.

At a higher experimental dose, the circulating insulin concentration increased approximately twofold (p < 0.001).

Histological analysis suggested a lesser severity of inflammation of the pancreas, the disappearance of the pancreatic islets, and the loss of beta cells.

The levels of oxidative stress also changed. The level of glutathione increased approximately 1.92-fold (p < 0.01), the level of malondialdehyde decreased to 81.9% of the value observed in the comparison group with diabetes (p < 0.05), and the activity of superoxide dismutase and catalase increased.

The results indicate possible anti-inflammatory and oxidative stress-related pathways, but they do not confirm Tα1 as a treatment method for diabetes [26].

Intestinal inflammation associated with checkpoint inhibitors and anti-tumor immunity

Renga and colleagues (2020) used mouse models to study intestinal inflammation caused by CTLA-4 blockade.

Tα1 reduced experimental colitis and tissue damage while maintaining the anti-tumor activity of the treatment blocking the control points.

Mechanistic studies indicated a tolerogenic pathway dependent on indoleamine-2,3-dioxygenase 1 (IDO1) in the gut, without concomitant increase of IDO1 in tumors.

Changes were also observed in the signaling of dendritic cells and in the balance between CD8⁺ T lymphocytes and regulatory T lymphocytes in the tumor environment.

The results indicate the possibility of separating the immunological toxicity in the intestines from the anti-cancer activity, but the clinical benefits and safety remain unconfirmed [27].

Systemic candidiasis under experimental immunosuppression conditions

Di Francesco and colleagues (1994) studied systemic infection Candida albicans in mice, including in animals whose immune functions have been weakened by morphine.

The experimental number of microorganisms used to infect the mice was 10⁶.

Combining Tα1 with fluconazole prolonged survival and reduced the fungal burden in the kidneys more than any of these interventions alone.

Researchers linked these effects to the restoration of antifungal activity of neutrophils, the function of NK cells, and changes in lymphocyte signaling.

Fluconazole was less effective in animals with resistance weakened by morphine, whereas the addition of Tα1 seemed to partially restore its activity.

The results are limited to an experimental model of infection and do not justify the clinical use of such an antifungal combination without appropriate studies [28].

How should the Tα1 dosing regimens described in the studies be interpreted?

Scientific literature describes various regimens for administering Tα1 depending on the disease, the study design, and the treatment conditions.

In several human studies, fixed subcutaneous doses of 1.6 mg were used, sometimes twice a week. In a study concerning platelet aggregation, the peptide was administered three times a week, while in some studies on acute clinical conditions or complications of chemotherapy, short cycles of daily administration were used.

In one study of severe pancreatitis, 3.2 mg twice daily was evaluated for seven days. In HIV adjunct therapy studies, weekly injections adjusted to body surface area were also analyzed, ranging from 400 to 1600 µg/m².

The periods of study described included both short hospital interventions and approximately 8–12 weeks in studies on immune reconstitution or depressive symptoms.

These values describe historical research protocols. They do not constitute a universal dose, recommended regimen, or evidence that Tα1 should be used in the experimental indications discussed in the article.

Treatment decisions depend on the local registration status, the quality of the product, the indication, the clinical situation, and the evaluation by the specialist.

What conclusions can be drawn from the available evidence?

Thymosin alfa-1 has a long history of research as an immunomodulatory peptide. The strongest human research results presented in this review relate to immune-related parameters in specific clinical situations, including severe acute pancreatitis.

The remaining indications are based on small clinical studies, post hoc analyses, uncontrolled reports, or laboratory experiments.

Improving cytokine parameters, markers of T lymphocytes, animal behavior, or cell function provides important biological information. However, this does not necessarily translate into a lower incidence of diseases, improved survival, or better quality of life.

Results regarding depression, fertility, anti-tumor response, neurological damage, diabetes, and mucopolysaccharidosis require particularly cautious interpretation.

The available data justify scientific interest, but do not allow for broad statements about confirmed clinical benefits.

Future studies should focus on appropriately large, randomized clinical trials with clinically relevant endpoints and transparent reporting of adverse events.

Editorial note: This article presents the results of published scientific studies and is not intended as a guide to prescribing, dosing, or self-administration of thymozine alfa-1. The clinical status of thymalfazine and the permitted indications for its use vary by country.

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